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Scopolamine-induced deficits in spontaneous alternation performance: Attenuation with lateral ventricle injections of glucose
BEHAVIORAL AND NEURAL BIOLOGY 57, 90-92 (1992)
BRIEF REPORT Scopolamine-Induced Deficits in Spontaneous Alternation Performance: Attenuation with Lateral Ventricle Injections of Glucose MICHAEL W. PARSONS 1 AND PAUL
E. GOLD2
Department of Psychology, Life Sciences Laboratories, University of Virginia, Charlottesville, Virginia 22903
hormone on memory. One peripheral consequence of increases in circulating epinephrine is an increase in blood-glucose levels (Ellis, Kennedy, Eusebi, & Vincent, 1967). Substantial evidence now suggests that increases in blood-glucose levels m a y mediate epinephrine effects on memory (for reviews see Gold, 1991; White, 1991). Like epinephrine, post-training administration of glucose enhances memory at doses which result in blood-glucose levels comparable to those seen after effective epinephrine injections. Glucose also enhances memory for several classes of training procedures, including inhibitory avoidance, classical conditioning, and operant tasks in rodents, and verbal memory tests in humans. Thus, glucose may serve as an important intermediate step between epinephrine release and effects on brain function responsible for regulating the storage of new information. Unlike epinephrine, glucose gains ready access from blood to the central nervous system via a facilitated uptake mechanism (Oldendorf, 1971), raising the possibility t h a t glucose acts on memory by direct central actions. Indirect evidence supporting this view comes from a series of experiments which examined glucose interactions with central neurotransmitter functions. The results of these experiments indicate t h a t peripheral injections of glucose attenuate the effects of cholinergic antagonists and a u g m e n t the effects of cholinergic antagonists on such measures as memory, sleep, locomotor activity, tremors, and 2-deoxyglucose uptake (cf. Gold, 1991). For example, glucose attenuates scopolamine-induced memory impairments for inhibitory avoidance and spontaneous alternation performance. More direct evidence t h a t glucose acts directly on the brain to enhance m e m o r y comes from findings
This experiment determined whether centrally administered glucose can attenuate scopolainine-induced deficits in spontaneous alternation performance. All rats were surgically prepared with indwelling cannulae directed at the lateral ventricle. Thirty rain prior to alternation tests, rats received systemic (ip) injections of saline or scopolamine (3 mg/kg). Ten or thirty min prior to training, the rats also received a direct injection into the lateral ventricle of either artificial cerebrospinal fluid (CSF) or glucose (3 ~g in 1 ~l). Scopolamine significantly impaired spontaneous alternation performance relative to controls. Additional treatment with ICV glucose 30 min, but not 10 min prior to testing, significantly attenuated the scopolamine-induced deficit. These results add support to the view that glucose acts directly on brain systems to attenuate behavioral effects of cholinergic antagonists. © 1992 Academic Press, Inc.
When injected systemically or released into the circulation from the adrenal medulla, epinephrine regulates memory storage processing (cf. McGaugh, 1989). The evidence includes demonstrations that post-training administration of epinephrine enhances memory for a wide range of learned responses, including performance tested in avoidance and appetitive tasks. Furthermore, post-training plasma-epinephrine levels predict later retention performance in rats under several conditions. Because circulating epinephrine is largely excluded from the central nervous system, it is likely that peripheral actions mediate the effects of the Present address: The Department of Psychology,University of Texas, Austin, TX 78712. 2 This work was supported by research grants from ONR (N0001489-J-1216), NIA (AG 07648), and NSF (BNS-9012239). Address reprint requests to Dr. Paul E. Gold. 90 0163-1047/92 $3.00 Copyright © 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
91
GLUCOSE EFFECTS ON MEMORY
that post-training injections of glucose directly into the lateral cerebral ventricle enhance memory (Lee, Graham, & Gold, 1988). The present experiment integrated the two strategies-pharmacological interactions and direct brain injections--to determine whether intraventricular glucose injections would reverse the effects of systemically administered scopolamine on spontaneous alternation performance. Male S p r a g u e - D a w l e y rats (300-500 g, Hilltop Laboratories) were used in this experiment. The rats were housed individually with free access to food and water. The rats were maintained on a 12-hr light/dark cycle (0700-1900 on) for at least 1 week prior to the start of the experiment and thereafter. One week prior to behavioral testing, rats were anesthetized (Nembutal, 45 mg/kg) and prepared with indwelling chronic cannulae aimed at the lateral ventricle through which intracerebroventricular (ICV) injections could be administered. Outer guide cannulae (22 g, stainless steel, 3.8 mm long; Plastic Products Model C313G) were stereotaxically placed in the lateral ventricle (AP = 0.0 mm, L = 1.5 mm, V = 2.8 mm below dura, skull horizontal). Two screws were placed in the skull to serve as anchors for the acrylic cement mounting. The guide cannula was occluded with a d u m m y inner cannula (32 g) cut to the same length as the guide. At the conclusion of surgery, each rat received an injection of Bicillin (60,000 units, im). Spontaneous alternation tests were conducted 1 2 weeks after surgery. The doses used for peripheral injections of scopolamine and central injections of glucose were based on those identified in previous studies (Lee, Graham, & Gold, 1988; Gold, 1991). All rats received ip injections of either scopolamine (3 mg/kg) or saline 30 min prior to testing. Immediately or 20 min later, each rat received an ICV injection (Razel syringe pump, rate = 1/~1/3 min) ,of artificial cerebrospinal fluid (CSF) or glucose (3 ,~g in 1/~1). The time of the second injection did not influence alternation behavior in the groups that received saline (ip) and CSF (ICV) (N = 8, means = 73.3 and 72.0), saline and glucose (N = 5, means = 74.3 and 74.8), or scopolamine and CSF (51.0 and 54.6, respectively). Therefore, the results in these groups were pooled by time of injection for statistical comparisons described below. Thus, the design included the following groups: s a l i n e - C S F (N = 10), saline-glucose (N = 10), and scopolamine-CSF (N = 16). In the two additional groups, scopolamine was administered 30 min before testing and glucose was administered either 30 or 10 min before testing
z
0 p<~ Z Od
w~
8O • P
< 6
D
U ~ 6o rY L~ O_
z
50
Ld
4O PERIPHERAL:
SAL
SAL
CENTRAL:
CSF
OLU
SCOP SCOP SCOP CSF
GLU
OLU
10 min 30 m~n
FIG. 1. Attenuation of scopolamine (ip)-induced deficits in spontaneous alternation performance with central (ICV) injections of glucose. Note that glucose administered 30 min prior to testing, i.e., at the time of the peripheral scopolamine injection, significantly improved performance above that of the scopolamine-CSF group.
(N's = 8 and 11, respectively). Results for these groups are presented separately. Spontaneous alternation performance was assessed in a trough-shaped Y-maze. Stainless steel plates constituted the walls and floor and dark translucent Plexiglass covered the apparatus. Each arm was 60 cm long, 17.5 cm high, 3.5 cm wide at the bottom, and 14 cm wide at the top. The arms converged at a triangular central area that was 4 cm along its longest axis. The testing procedure was based on that of Sarter, Bodewitz and Stephens (1988). Rats were placed in one arm and allowed to move freely through the maze for an 8-min test session. The sequence of arm entries was recorded manually. An alternation was defined as entry into all three arms on consecutive choices. The number of possible alternations was then defined as the total number of arm entries minus two, and the alternation percentage calculated as: [number of alternations / (number of possible alternations - 2)] x 100. Statistical comparisons between groups were made with two-tailed t tests. After completion of the spontaneous alternation tests, the animals were deeply anesthetized and received an ICV injection of dye (10/~l). The rats were then decapitated and distribution of dye into the ventricles was determined visually, Animals without dye in the ventricles were excluded from statistical analyses (n = 13). The findings of this experiment are shown in Figure 1. Peripheral scopolamine injections resulted in
92
PARSONS AND GOLD
a significant deficit in spontaneous alternation performance (scopolamine-CSF vs saline-CSF, t = 5.26, d f = 23, P < 0.001). When administered 30 min prior to testing, ICV injections of glucose significantly attenuated this deficit (t = 2.58, d f = 22, P < 0.02). Performance of this group was below that of the saline-CSF group but this difference was not statistically significant (t = 1.67, d f = 15, P < 0.2). Glucose did not significantly attenuate the scopolamine-induced deficit when administered 10 min prior to testing (t = 1.36, d f = 25, P < 0.2). ICV injections of glucose after saline administration did not significantly change spontaneous alternation performance. There were no significant differences across groups in the numbers of arms entered. For example, mean ( _ SEM) number of arm entries in scopolamine-glucose (10 min) and scopolamineCSF groups were 17 -+ 2 and 19 + 2, respectively. Peripheral scopolamine injections impaired performance on the spontaneous alternation task employed here. These findings are consistent with previous reports of scopolamine-induced impairments on several tasks which include elements of spatial and learned responses (e.g., Okaichi, Oshima, Jarrard, & Doshisha, 1989; Decker, Gill, & McGaugh, 1990). ICV injections of glucose, administered at the time of peripheral scopolamine administration (30 min prior to testing), significantly attenuated the scopolamine-induced deficit in spontaneous alternation testing. This finding is analogous to those in which we found that peripherally administered glucose attenuates scopolamine effects, and augments physostigmine effects, on several behavioral and neural measures (cf. Gold, 1991). Thus, the findings of the present experiment add to past evidence that glucose interacts with cholinergic drugs by attenuating the effects of cholinergic antagonists and potentiating the effects of cholinergic agonists. The present findings are also consistent with the previous demonstration that post-training ICV injections of glucose enhance memory for inhibitory avoidance training (Lee, Graham, & Gold, 1988). Because ICV glucose injections are effective in attenuating spontaneous alternation deficits produced by scopolamine, the findings suggest that circulating glucose, with its ready access to the central nervous system via a facilitated transport meChanism (Oldendorf, 1971), acts directly on the central nervous system to reverse the actions of the muscarinic antagonist. The results do not, however, distinguish between direct actions on cholinergic neurons, indirect actions mediated through alterations
in cholinergic functions, and other actions mediated by parallel s y s t e m s . The nature of the distribution of glucose from the ventricles to brain sites at which glucose might act is not known. Other evidence from this laboratory suggests that glucose m a y augment cholinergic functions indirectly by decreasing opiate (and GABA) inhibition of cholinergic neurons. One brain area in which such neurotransmitter interactions are likely is the medial septum, from which cholinergic afferents to the hippocampus are largely derived. Initial evidence suggests that glucose administered directly into medial septum attenuates the effects of intraseptal or peripheral administration of morphine (Ragozzino & Gold, 1991), in general agreement with the present findings suggesting that glucose acts centrally to regulate memory and other brain functions. REFERENCES Decker, M. W., Gill, T. M., & McGaugh, J. L. (1990). Concurrent muscarinic and ~-adrenergic blockade in rats impairs placelearning in a water maze and retention of inhibitory avoidance. Brain Research, 513, 81-85. Ellis, S., Kennedy, B. L., Eusebi, A. J., & Vincent, N. H. (1967). Autonomic control of metabolism. Annals of the New York Academy of Science, 139, 826-832. Gold, P. E. (1991). An integrated memory regulation system: From blood to brain. In R.C.A. Frederickson, J. L. McGaugh, & D. L. Felten (Eds.), Peripheral signaling of the brain: Role in neural-immune interactions, learning and memory, pp. 391-419. Hogrefe & Huber, Toronto.
Lee, M., Graham, S., & Gold, P. E. (1988). Memoryenhancement with posttraining intraventricular glucose injections in rats. Behavioral Neuroscience, 102, 591-595. McGaugh, J. L. (1989). Involvement of hormonal and neuromodulatory systems in the regulation of memory storage. Annual Review of Neuroscience, 12, 255-287. Okaichi, H., Oshima, Y., Jarrard, L. E., & Doshisha, U. (1989). Scopolamine impairs both working and reference memory in rats: A replication and extension. Pharmacology, Biochemistry, and Behavior, 34, 599-602. Oldendorf, W. H. (1971). Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. American Journal of Physiology, 221, 1629-1639. Ragozzino, M., & Gold, P. E. (1991).Peripheral and medial septal injections of glucose attenuate impaired spontaneous alternation performance produced by intraseptal morphine injections. In preparation. Sarter, M., Bodewitz, G., & Stephens, D. N. (1988). Attenuation of scopolamine-induced impairment of spontaneous alternation behavior by antagonist but not inverse antagonist and agonist B-carbolines.Psychopharmacology, 94, 491-495. White, N. M. (1991). Peripheral and central memory-enhancing actions of glucose. In R. C. A. Frederickson, J. L. McGaugh, & D. L. Felten (Eds.), Peripheral signaling of the brain: Role in neural-immune interactions and learning and memory (pp. 421-441). Toronto: Hogrefe & Huber.
BRIEF REPORT Scopolamine-Induced Deficits in Spontaneous Alternation Performance: Attenuation with Lateral Ventricle Injections of Glucose MICHAEL W. PARSONS 1 AND PAUL
E. GOLD2
Department of Psychology, Life Sciences Laboratories, University of Virginia, Charlottesville, Virginia 22903
hormone on memory. One peripheral consequence of increases in circulating epinephrine is an increase in blood-glucose levels (Ellis, Kennedy, Eusebi, & Vincent, 1967). Substantial evidence now suggests that increases in blood-glucose levels m a y mediate epinephrine effects on memory (for reviews see Gold, 1991; White, 1991). Like epinephrine, post-training administration of glucose enhances memory at doses which result in blood-glucose levels comparable to those seen after effective epinephrine injections. Glucose also enhances memory for several classes of training procedures, including inhibitory avoidance, classical conditioning, and operant tasks in rodents, and verbal memory tests in humans. Thus, glucose may serve as an important intermediate step between epinephrine release and effects on brain function responsible for regulating the storage of new information. Unlike epinephrine, glucose gains ready access from blood to the central nervous system via a facilitated uptake mechanism (Oldendorf, 1971), raising the possibility t h a t glucose acts on memory by direct central actions. Indirect evidence supporting this view comes from a series of experiments which examined glucose interactions with central neurotransmitter functions. The results of these experiments indicate t h a t peripheral injections of glucose attenuate the effects of cholinergic antagonists and a u g m e n t the effects of cholinergic antagonists on such measures as memory, sleep, locomotor activity, tremors, and 2-deoxyglucose uptake (cf. Gold, 1991). For example, glucose attenuates scopolamine-induced memory impairments for inhibitory avoidance and spontaneous alternation performance. More direct evidence t h a t glucose acts directly on the brain to enhance m e m o r y comes from findings
This experiment determined whether centrally administered glucose can attenuate scopolainine-induced deficits in spontaneous alternation performance. All rats were surgically prepared with indwelling cannulae directed at the lateral ventricle. Thirty rain prior to alternation tests, rats received systemic (ip) injections of saline or scopolamine (3 mg/kg). Ten or thirty min prior to training, the rats also received a direct injection into the lateral ventricle of either artificial cerebrospinal fluid (CSF) or glucose (3 ~g in 1 ~l). Scopolamine significantly impaired spontaneous alternation performance relative to controls. Additional treatment with ICV glucose 30 min, but not 10 min prior to testing, significantly attenuated the scopolamine-induced deficit. These results add support to the view that glucose acts directly on brain systems to attenuate behavioral effects of cholinergic antagonists. © 1992 Academic Press, Inc.
When injected systemically or released into the circulation from the adrenal medulla, epinephrine regulates memory storage processing (cf. McGaugh, 1989). The evidence includes demonstrations that post-training administration of epinephrine enhances memory for a wide range of learned responses, including performance tested in avoidance and appetitive tasks. Furthermore, post-training plasma-epinephrine levels predict later retention performance in rats under several conditions. Because circulating epinephrine is largely excluded from the central nervous system, it is likely that peripheral actions mediate the effects of the Present address: The Department of Psychology,University of Texas, Austin, TX 78712. 2 This work was supported by research grants from ONR (N0001489-J-1216), NIA (AG 07648), and NSF (BNS-9012239). Address reprint requests to Dr. Paul E. Gold. 90 0163-1047/92 $3.00 Copyright © 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
91
GLUCOSE EFFECTS ON MEMORY
that post-training injections of glucose directly into the lateral cerebral ventricle enhance memory (Lee, Graham, & Gold, 1988). The present experiment integrated the two strategies-pharmacological interactions and direct brain injections--to determine whether intraventricular glucose injections would reverse the effects of systemically administered scopolamine on spontaneous alternation performance. Male S p r a g u e - D a w l e y rats (300-500 g, Hilltop Laboratories) were used in this experiment. The rats were housed individually with free access to food and water. The rats were maintained on a 12-hr light/dark cycle (0700-1900 on) for at least 1 week prior to the start of the experiment and thereafter. One week prior to behavioral testing, rats were anesthetized (Nembutal, 45 mg/kg) and prepared with indwelling chronic cannulae aimed at the lateral ventricle through which intracerebroventricular (ICV) injections could be administered. Outer guide cannulae (22 g, stainless steel, 3.8 mm long; Plastic Products Model C313G) were stereotaxically placed in the lateral ventricle (AP = 0.0 mm, L = 1.5 mm, V = 2.8 mm below dura, skull horizontal). Two screws were placed in the skull to serve as anchors for the acrylic cement mounting. The guide cannula was occluded with a d u m m y inner cannula (32 g) cut to the same length as the guide. At the conclusion of surgery, each rat received an injection of Bicillin (60,000 units, im). Spontaneous alternation tests were conducted 1 2 weeks after surgery. The doses used for peripheral injections of scopolamine and central injections of glucose were based on those identified in previous studies (Lee, Graham, & Gold, 1988; Gold, 1991). All rats received ip injections of either scopolamine (3 mg/kg) or saline 30 min prior to testing. Immediately or 20 min later, each rat received an ICV injection (Razel syringe pump, rate = 1/~1/3 min) ,of artificial cerebrospinal fluid (CSF) or glucose (3 ,~g in 1/~1). The time of the second injection did not influence alternation behavior in the groups that received saline (ip) and CSF (ICV) (N = 8, means = 73.3 and 72.0), saline and glucose (N = 5, means = 74.3 and 74.8), or scopolamine and CSF (51.0 and 54.6, respectively). Therefore, the results in these groups were pooled by time of injection for statistical comparisons described below. Thus, the design included the following groups: s a l i n e - C S F (N = 10), saline-glucose (N = 10), and scopolamine-CSF (N = 16). In the two additional groups, scopolamine was administered 30 min before testing and glucose was administered either 30 or 10 min before testing
z
0 p<~ Z Od
w~
8O • P
< 6
D
U ~ 6o rY L~ O_
z
50
Ld
4O PERIPHERAL:
SAL
SAL
CENTRAL:
CSF
OLU
SCOP SCOP SCOP CSF
GLU
OLU
10 min 30 m~n
FIG. 1. Attenuation of scopolamine (ip)-induced deficits in spontaneous alternation performance with central (ICV) injections of glucose. Note that glucose administered 30 min prior to testing, i.e., at the time of the peripheral scopolamine injection, significantly improved performance above that of the scopolamine-CSF group.
(N's = 8 and 11, respectively). Results for these groups are presented separately. Spontaneous alternation performance was assessed in a trough-shaped Y-maze. Stainless steel plates constituted the walls and floor and dark translucent Plexiglass covered the apparatus. Each arm was 60 cm long, 17.5 cm high, 3.5 cm wide at the bottom, and 14 cm wide at the top. The arms converged at a triangular central area that was 4 cm along its longest axis. The testing procedure was based on that of Sarter, Bodewitz and Stephens (1988). Rats were placed in one arm and allowed to move freely through the maze for an 8-min test session. The sequence of arm entries was recorded manually. An alternation was defined as entry into all three arms on consecutive choices. The number of possible alternations was then defined as the total number of arm entries minus two, and the alternation percentage calculated as: [number of alternations / (number of possible alternations - 2)] x 100. Statistical comparisons between groups were made with two-tailed t tests. After completion of the spontaneous alternation tests, the animals were deeply anesthetized and received an ICV injection of dye (10/~l). The rats were then decapitated and distribution of dye into the ventricles was determined visually, Animals without dye in the ventricles were excluded from statistical analyses (n = 13). The findings of this experiment are shown in Figure 1. Peripheral scopolamine injections resulted in
92
PARSONS AND GOLD
a significant deficit in spontaneous alternation performance (scopolamine-CSF vs saline-CSF, t = 5.26, d f = 23, P < 0.001). When administered 30 min prior to testing, ICV injections of glucose significantly attenuated this deficit (t = 2.58, d f = 22, P < 0.02). Performance of this group was below that of the saline-CSF group but this difference was not statistically significant (t = 1.67, d f = 15, P < 0.2). Glucose did not significantly attenuate the scopolamine-induced deficit when administered 10 min prior to testing (t = 1.36, d f = 25, P < 0.2). ICV injections of glucose after saline administration did not significantly change spontaneous alternation performance. There were no significant differences across groups in the numbers of arms entered. For example, mean ( _ SEM) number of arm entries in scopolamine-glucose (10 min) and scopolamineCSF groups were 17 -+ 2 and 19 + 2, respectively. Peripheral scopolamine injections impaired performance on the spontaneous alternation task employed here. These findings are consistent with previous reports of scopolamine-induced impairments on several tasks which include elements of spatial and learned responses (e.g., Okaichi, Oshima, Jarrard, & Doshisha, 1989; Decker, Gill, & McGaugh, 1990). ICV injections of glucose, administered at the time of peripheral scopolamine administration (30 min prior to testing), significantly attenuated the scopolamine-induced deficit in spontaneous alternation testing. This finding is analogous to those in which we found that peripherally administered glucose attenuates scopolamine effects, and augments physostigmine effects, on several behavioral and neural measures (cf. Gold, 1991). Thus, the findings of the present experiment add to past evidence that glucose interacts with cholinergic drugs by attenuating the effects of cholinergic antagonists and potentiating the effects of cholinergic agonists. The present findings are also consistent with the previous demonstration that post-training ICV injections of glucose enhance memory for inhibitory avoidance training (Lee, Graham, & Gold, 1988). Because ICV glucose injections are effective in attenuating spontaneous alternation deficits produced by scopolamine, the findings suggest that circulating glucose, with its ready access to the central nervous system via a facilitated transport meChanism (Oldendorf, 1971), acts directly on the central nervous system to reverse the actions of the muscarinic antagonist. The results do not, however, distinguish between direct actions on cholinergic neurons, indirect actions mediated through alterations
in cholinergic functions, and other actions mediated by parallel s y s t e m s . The nature of the distribution of glucose from the ventricles to brain sites at which glucose might act is not known. Other evidence from this laboratory suggests that glucose m a y augment cholinergic functions indirectly by decreasing opiate (and GABA) inhibition of cholinergic neurons. One brain area in which such neurotransmitter interactions are likely is the medial septum, from which cholinergic afferents to the hippocampus are largely derived. Initial evidence suggests that glucose administered directly into medial septum attenuates the effects of intraseptal or peripheral administration of morphine (Ragozzino & Gold, 1991), in general agreement with the present findings suggesting that glucose acts centrally to regulate memory and other brain functions. REFERENCES Decker, M. W., Gill, T. M., & McGaugh, J. L. (1990). Concurrent muscarinic and ~-adrenergic blockade in rats impairs placelearning in a water maze and retention of inhibitory avoidance. Brain Research, 513, 81-85. Ellis, S., Kennedy, B. L., Eusebi, A. J., & Vincent, N. H. (1967). Autonomic control of metabolism. Annals of the New York Academy of Science, 139, 826-832. Gold, P. E. (1991). An integrated memory regulation system: From blood to brain. In R.C.A. Frederickson, J. L. McGaugh, & D. L. Felten (Eds.), Peripheral signaling of the brain: Role in neural-immune interactions, learning and memory, pp. 391-419. Hogrefe & Huber, Toronto.
Lee, M., Graham, S., & Gold, P. E. (1988). Memoryenhancement with posttraining intraventricular glucose injections in rats. Behavioral Neuroscience, 102, 591-595. McGaugh, J. L. (1989). Involvement of hormonal and neuromodulatory systems in the regulation of memory storage. Annual Review of Neuroscience, 12, 255-287. Okaichi, H., Oshima, Y., Jarrard, L. E., & Doshisha, U. (1989). Scopolamine impairs both working and reference memory in rats: A replication and extension. Pharmacology, Biochemistry, and Behavior, 34, 599-602. Oldendorf, W. H. (1971). Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. American Journal of Physiology, 221, 1629-1639. Ragozzino, M., & Gold, P. E. (1991).Peripheral and medial septal injections of glucose attenuate impaired spontaneous alternation performance produced by intraseptal morphine injections. In preparation. Sarter, M., Bodewitz, G., & Stephens, D. N. (1988). Attenuation of scopolamine-induced impairment of spontaneous alternation behavior by antagonist but not inverse antagonist and agonist B-carbolines.Psychopharmacology, 94, 491-495. White, N. M. (1991). Peripheral and central memory-enhancing actions of glucose. In R. C. A. Frederickson, J. L. McGaugh, & D. L. Felten (Eds.), Peripheral signaling of the brain: Role in neural-immune interactions and learning and memory (pp. 421-441). Toronto: Hogrefe & Huber.